Submissions for variant NM_000051.4(ATM):c.7630-1G>A

dbSNP: rs2086285148

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245396	SCV001418681	pathogenic	Ataxia-telangiectasia syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 51 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 9443866, 9887333, 21833744, 25374739, 26681312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 969935). Studies have shown that disruption of this splice site results in skipping of exon 52 and activation of a cryptic splice site and introduces a premature termination codon (PMID: 9887333; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002393650	SCV002673554	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-29	criteria provided, single submitter	clinical testing	The c.7630-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 51 of the ATM gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same acceptor site (c.7630-2A>G) has been shown to have a similar impact on splicing and has been detected in an individual with ataxia telangiectasia (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV003469471	SCV004212094	likely pathogenic	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003469471	SCV004931944	pathogenic	Familial cancer of breast	2024-02-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9443866, 9887333, 10330348]. Functional studies indicate this variant impacts protein function [PMID: 9443866, 9887333, 10330348].